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The seventh edition of this book is a comprehensive guide to biochemistry for medical students. Divided into six sections, the book examines in. Textbook of Biochemistry for Medical Students. Front Cover. Vasudevan D. M.. Jaypee Brothers, - pages. 0 Reviews. DM Vasudevan MBBS MD FAMS FRC (Path) Distinguished Professor of Biochemistry & Principal (Retired), College of Medicine; Amrita Institute of Medical.
Biochemical Perspective to Medicine Subcellular Organelles and Cell Membranes Amino Acids: Structure and Properties Structure and Function General Concepts and Enzyme Kinetics Chemistry of Carbohydrates Chemistry of Lipids Overview of Metabolism Major Metabolic Pathways of Glucose Minor Metabolic Pathways of Carbohydrates Metabolism of Fatty Acids Cholesterol and Lipoproteins One carbon compounds, Generation and utilization of one carbon groups.
Citric Acid Cycle Contents xiii Biological Oxidation and Electron Transport Chain Free Radicals and Anti-Oxidants Heme Synthesis and Breakdown Clinical Enzymology and Biomarkers Cardiovascular Diseases and Hyperlipidemias Liver and Gastric Function Tests Kidney Function Tests Plasma Proteins Acid-Base Balance and pH Electrolyte and Water Balance Clinical Laboratory: Screening of Metabolic Diseases; Quality Control Mineral Metabolism and Abnormalities Energy Metabolism and Nutrition Detoxification and Biotransformation of Xenobiotics Contents xv Environmental Pollution and Heavy Metal Poisons Nucleotides; Chemistry and Metabolism Structure and Replication Transcription and Translation Inheritance, Mutations and Control of Gene Expression Mechanisms of Action of Hormones Hypothalamic and Pituitary Hormones Steroid Hormones Thyroid Hormones Signal Molecules and Growth Factors Biochemistry of Cancer Tissue Proteins in Health and Disease Applications of Isotopes in Medicine General Techniques for Separation, Purification and Quantitation Contents xvii Molecular Diagnostics Abbreviations Used in this book Normal values Reference values Conversion Chart Greek Alphabet Commonly Used letters as Symbols History of biochemistry 2.
Biomolecules and metabolism 3. Ionic bonds 4. Hydrogen bonding 5. Hydrophobic interactions 6. Principles of thermodynamics 7. Donnan membrane equilibrium. Biochemical Perspective to Medicine The word chemistry is derived from the Greek word "chemi" the black land , the ancient name of Egypt. Indian medical science, even from ancient times, had identified the metabolic and genetic basis of diseases. Charaka, the great master of Indian Medicine, in his treatise circa BC observed that madhumeha diabetes mellitus is produced by the alterations in the metabolism of carbohydrates and fats; the statement still holds good.
Biochemistry has developed as an offshoot of organic chemistry, and this branch was often referred as "physiological chemistry". One of the earliest treatises in biochemistry was the "Book of Organic Chemistry and its Applications to Physiology and Pathology", published in by Justus von Liebig , who introduced the concept of metabolism.
The "Textbook of Physiological Chemistry" was published in by Felix Hoppe-Seyler , who was professor of physiological chemistry at Strausbourge University, France. Some of the milestones in the development of science of biochemistry are given in Table 1.
The practice of medicine is both an art and a science. The word "doctor" is derived from the Latin root, "docere", which means "to teach". Knowledge devoid of ethical background may sometimes be disastrous! About one century earlier, Sushrutha BC , the great Indian surgeon, enunciated a code of conduct to the medical practitioners, which is still valid.
He proclaims: No wonder, the major share of Nobel prizes in medicine has gone to research workers engaged in biochemistry. Thanks to the advent of DNA-recombination technology, genes can now be transferred from one person to another, so that many of the genetically determined diseases are now amenable to gene therapy.
Many genes, e. Advances in genomics like RNA interference for silencing of genes and creation of transgenic animals by gene targeting of embryonic stem cells are opening up new vistas in therapy of diseases like cancer and AIDS. It is hoped that in future, physician will be able to treat the patient, understanding his genetic basis, so that very efficient "designer medicine" could cure the diseases. The large amount of data, especially with regard to single.
Biochemistry is the language of biology. The tools for research in all the branches of medical science are based on principles of biochemistry.
The study of biochemistry is essential to understand basic functions of the body. This will give information regarding the functioning of cells at the molecular level.
How the food that we eat is digested, absorbed, and used to make ingredients of the body? How does the body derive energy for the normal day to day work?
How are the various metabolic processes interrelated? What is the function of genes? What is the molecular basis for immunological resistance against invading organisms? Answer for such basic questions can only be derived by a systematic study of medical biochemistry. Modern day medical practice is highly dependent on the laboratory analysis of body fluids, especially the blood.
The disease manifestations are reflected in the composition of blood and other tissues. Hence, the demarcation of abnormal from normal constituents of the body is another aim of the study of clinical biochemistry.
Table 1. Computers are already helping in drug designing process. Studies on oncogenes have identified molecular mechanisms of control of normal and abnormal cells. Medical practice is now taking more and more help from the field of biochemistry. With the help of human genome project HGP the sequences of the whole human genes are now available; it has already made great impact on medicine and related health sciences.
Molecular structures in organisms are built from 30 small precursors, sometimes called the alphabet of biochemistry.
These are 20 amino acids, 2 purines, 3 pyrimidines, sugars glucose and ribose , palmitate, glycerol and choline. In living organisms the biomolecules are ordered into a hierarchy of increasing molecular complexity. These biomolecules are covalently. Major complex biomolecules are Proteins, Polysaccharides, Lipids and Nucleic acids. The macromolecules associate with each other by noncovalent forces to form supramolecular systems, e.
Finally, at the highest level of organisation in the hierarchy of cell structure, various supramolecular complexes are further assembled into cell organelle. In prokaryotes e. Comparison of prokaryotes and eukaryotes are shown in Table 1. These macromolecules are Table 1. Bacterial and mammalian cells Size Prokaryotic cell Eukaryotic cell Small Large; to 10, times Rigid Membrane of lipid bilayer Not defined Well defined Several; including mitochondria and lysosomes.
Ionic bonds used in protein interactions group of histidine. Negative charges are provided by beta and gamma carboxyl groups of aspartic acid and glutamic acid Fig. Hydrogen Bonds These are formed by sharing of a hydrogen between two electron donors. Hydrogen bonds result from electrostatic attraction between an electro-negative atom and a hydrogen atom that is bonded covalently to a second electronegative atom.
Normally, a hydrogen atom forms a covalent bond with only one other atom. However, a hydrogen atom covalently bonded to a donor atom, may form an additional weak association, the hydrogen bond with an acceptor atom. In biological systems, both donors and acceptors are usually nitrogen or oxygen atoms, especially those atoms in amino NH2 and hydroxyl OH groups.
With regard to protein chemistry, hydrogen releasing groups are -NH imidazole, indole, peptide ; -OH serine, threonine and -NH2 arginine lysine. The DNA structure is maintained by hydrogen bonding between the purine and pyrimidine residues. This process is taking place in the gastrointestinal tract and is called digestion or primary metabolism.
After absorption, the small molecules are further broken down and oxidised to carbon dioxide. This is named as secondary or intermediary metabolism. Finally, these reducing equivalents enter the electron transport chain in the mitochondria, where they are oxidised to water; in this process energy is trapped as ATP. This is termed tertiary metabolism. Metabolism is the sum of all chemical changes of a compound inside the body, which includes synthesis anabolism and breakdown catabolism.
Covalent Bonds Molecules are formed by sharing of electrons between atoms Fig. Ionic Bonds or Electrostatic Bonds Ionic bonds result from the electrostatic attraction between two ionized groups of opposite charges Fig. They are formed by transfer of one or more electrons from the outermost orbit of an electropositive atom to the outermost orbit of an electronegative atom. This transfer results in the formation of a cation and an anion, which get consequently bound by an ionic bond.
With regard to protein chemistry, positive charges are produced by epsilon amino group of lysine, guanidium group of arginine and imidazolium.
Hydrophobic Interactions Non-polar groups have a tendency to associate with each other in an aqueous environment; this is referred to as hydrophobic interaction. These are formed by interactions between nonpolar hydrophobic side chains by eliminating water molecules.
The force that causes hydrophobic molecules or nonpolar portions of molecules to aggregate together rather than to dissolve in water is called the hydrophobic bond Fig. This serves to hold lipophilic side chains of amino acids together. Thus, nonpolar molecules will have minimum exposure to water molecules. Van Der Waals Forces These are very weak forces of attraction between all atoms, due to oscillating dipoles, described by the Dutch physicist Johannes van der Waals He was awarded Nobel prize in These are short range attractive forces between chemical groups in contact.
Van der Waals interactions occur in all types of molecules, both polar and nonpolar. This force will drastically reduce, when the distance between atoms is increased.
Although very weak, van der Waals forces collectively contribute maximum towards the stability of protein structure, especially in preserving the nonpolar interior structure of proteins. The hydrogen atom in one water molecule is attracted to a pair of electrons in the outer shell of an oxygen atom in an adjacent molecule.
The structure of liquid water contains hydrogen-bonded networks Fig. The crystal structure of ice depicts a tetrahedral arrangement of water molecules. Four others bound by hydrogen bonds surround each oxygen atom.
On melting, the molecules get much closer and this results in the increase in density of water. Hence, liquid water is denser than solid ice.
This also explains why ice floats on water. Water molecules are in rapid motion, constantly making and breaking hydrogen bonds with adjacent molecules. As the temperature of water increases. Water molecules hydrogen bonded toward C, the kinetic energy of its molecules becomes greater than the energy of the hydrogen bonds connecting them, and the gaseous form of water appears.
A few gifted properties of water make it the most preferred medium for all cellular reactions and interactions. Water is a polar molecule. Molecules with polar bonds that can easily form hydrogen bonds with water can dissolve in water and are termed hydrophilic. It has immense hydrogen bonding capacity both with other molecules and also the adjacent water molecules. This contributes to cohesiveness of water. Water favors hydrophobic interactions and provides a basis for metabolism of insoluble substances.
Water expands when it is cooled from 4oC to o 0 C, while normally liquids are expected to contract due to cooling. As water is heated from 0oC to 4 oC, the hydrogen bonds begin to break. This results in a decrease in volume or in other words, increase in density. Hence, water attains high density at 4oC. However, above 4oC the effect of temperature predominates.
Bioenergetics, or biochemical thermodynamics, is the study of the energy changes accompanying biochemical reactions. Biological systems use chemical energy to power living processes. First Law of Thermodynamics The total energy of a system, including its surroundings, remains constant. This is also called the law of conservation of energy. If heat is transformed into work, there is proportionality between the work obtained and the heat dissipated.
A system is an object or a quantity of matter, chosen for observation. All other parts of the universe, outside the boundary of the system, are called the surroundings. Second Law of Thermodynamics The total entropy of a system must increase if a process is to occur spontaneously. A reaction occurs spontaneously if E is negative, or if the entropy of the system increases. Entropy S is a measure of the degree of randomness or disorder of a system.
Entropy becomes maximum in a system as it approaches true equilibrium. Enthalpy is the heat content of a system and entropy is that fraction of enthalpy which is not available to do useful work. A closed system approaches a state of equilibrium. Any system can spontaneously proceed from a state of low probability ordered state to a state of high probability disordered state.
The entropy of a system may decrease with an increase in that of the surroundings. Gibb's Free Energy Concept The term free energy is used to get an equation combining the first and second laws of thermodynamics. The term free energy denotes a portion of the total energy change in a system that is available for doing work.
For most biochemical reactions, it is seen that H is nearly equal to E. Hence, G or free energy of a system depends on the change in internal energy and change in entropy of a system. Standard Free Energy Change It is the free energy change under standard conditions. It is designated as G0. The standard conditions are defined for biochemical reactions at a pH of 7 and 1 M concentration, and differentiated by a priming sign G0. It is directly related to the equilibrium constant.
Actual free energy changes depend on reactant and product. Most of the reversible metabolic reactions are near equilibrium reactions and therefore their G is nearly zero.
The net rate of near equilibrium reactions are effectively regulated by the relative concentration of substrates and products. The metabolic reactions that function far from equilibrium are irreversible.
The velocity of these reactions are altered by changes in enzyme activity. A highly exergonic reaction is irreversible and goes to completion. Such a reaction that is part of a metabolic pathway, confers direction to the pathway and makes the entire pathway irreversible. Three Types of Reactions A.
A reaction can occur spontaneously when G is negative. Then the reaction is exergonic. If G is of great magnitude, the reaction goes to completion and is essentially irreversible. When G is zero, the system is at equilibrium.
For reactions where the G is positive, an input of energy is required to drive the reaction. The reaction is termed as endergonic. Examples given below. Similarly a reaction may be exothermic H is negative , isothermic H is zero or endothermic H is positive. Energetically unfavorable reaction may be driven forward by coupling it with a favorable reaction. But the 2nd reaction is coupled in the body, so that the reaction becomes possible.
When the two reactions are coupled in the reaction 3, the G 0 becomes Details on ATP and other high-energy phosphate bonds are described in Chapter Reactions of catabolic pathways degradation or oxidation of fuel molecules are usually exergonic,. Figs 1. Donnan membrane equilibrium whereas anabolic pathways synthetic reactions or building up of compounds are endergonic.
Metabolism constitutes anabolic and catabolic processes that are well co-ordinated. In Fig. Both ions can diffuse freely. Initially 5 molecules of NaR are added to the left compartment and 10 molecules of NaCl in the right compartment and both of them are ionized Fig. When equilibrium is reached, the distributions of ions are shown in Figure 1. Donnan's equation also states that the electrical neutrality in each compartment should be maintained.
In other words the number of cations should be equal to the number of anions, such that In left: In summary, Donnan's equations satisfy the following results: The products of diffusible electrolytes in both compartments are equal. The electrical neutrality of each compartment is maintained.
The total number of a particular type of ions before and after the equilibrium is the same. As a result, when there is non-diffusible anion on one side of a membrane, the diffusible cations are more, and diffusible anions are less, on that side. Clinical Applications of the Equation 1. The total concentration of solutes in plasma will be more than that of a solution of same ionic strength containing only diffusible ions; this provides the net osmotic gradient see under Albumin, in Chapter The lower pH values within tissue cells than in the surrounding fluids are partly due to the concentrations of negative protein ions within the cells being higher than in surrounding fluids.
The pH within red cells is lower than that of the surrounding plasma is due, in part, to the very high concentration of negative non-diffusible hemoglobin ions. The chloride shift in erythrocytes as well as higher concentration of chloride in CSF are also due to Donnan's effect Chapter Nucleus 2. Endoplasmic reticulum 3.
Golgi apparatus 4. Lysosomes 5. Mitochondria 6. Plasma membrane 7. Transport mechanisms 8. Simple and facilitated diffusion 9. Ion channels Active transport Uniport, symport and antiport. When the cell membrane is disrupted, either by mechanical means or by lysing the membrane by Tween a lipid solvent , the organized particles inside the cell are homogenised.
This is usually carried out in 0. The organelles could then be separated by applying differential centrifugal forces Table 2. Albert Claude got Nobel prize in for fractionating subcellular organelles. Marker Enzymes Some enzymes are present in certain organelles only; such specific enzymes are called as marker enzymes Table 2.
After centrifugation, the separated organelles are identified by detection of marker enzymes in the sample. It is the most prominent organelle of the cell. All cells in the body contain nucleus, except mature RBCs in circulation.
The uppermost layer of skin also may not possess a readily identifiable nucleus. In some cells, nucleus occupies most of the available space, e. Nucleus is surrounded by two membranes: The outer membrane is continuous with membrane of endoplasmic reticulum. Nucleus contains the DNA, the chemical basis of genes which governs all the functions of the cell. The very long DNA molecules are complexed with proteins to form chromatin and are further organized into chromosomes.
In some cells, a portion of the nucleus may be seen as lighter shaded area; this is called nucleolus Fig. This is the area for RNA processing and ribosome synthesis. The nucleolus is very prominent in cells actively synthesizing proteins.
Gabriel Valentine in described the nucleolus. It is a network of interconnecting membranes enclosing channels or cisternae, that are continuous from outer nuclear envelope to outer plasma membrane.
Under electron microscope, the reticular arrangements will have railway track appearance Fig. George Palade was awarded Nobel prize in , who identified the ER. Table 2. Separation of subcellular organelles Subcellular organelle Nucleus Mitochondria Lysosome Pellet formed at the centrifugal force of x g, 10 min 10,, x g, 10 min 18,, x g, 10 min Inner membrane: This will be very prominent in cells actively synthesizing proteins, e. The proteins, glycoproteins and lipoproteins are synthesized in the ER.
Detoxification of various drugs is an important function of ER. Microsomal cytochrome P hydroxylates drugs such as benzpyrine, aminopyrine, aniline, morphine, phenobarbitone, etc. According to the electron microscopic appearance, the ER is generally classified into rough and smooth varieties. The rough appearance is due to ribosomes attached to cytoplasmic side of membrane where the proteins are being synthesized. When cells are fractionated, the complex ER is disrupted in many places.
They are automatically re-assembled to form microsomes. Camillo Golgi described the structure in Nobel prize The Golgi organelle is a network of flattened smooth membranes and vesicles. It may be considered as the converging area of endoplasmic reticulum Fig. While moving through ER, carbohydrate groups are successively added to the nascent proteins.
These glycoproteins reach the Golgi area. Golgi apparatus is composed of cis, medial and trans cisternae. Glycoproteins are generally transported from ER to cis Golgi proximal cisterna , then to medial Golgi intermediate cisterna and finally to trans Golgi distal cisterna for temporary storage. Trans Golgi are particularly abundant with vesicles containing glycoproteins. Newly synthesized proteins are sorted first according to the sorting signals available in the proteins.
Then they are packed into transport vesicles having different types of coat proteins. Finally, they are transported into various destinations; this is an energy dependent process. Golgi complex 35,, x g, 30 min Microsomes Cytoplasm 75,, x g, min Supernatant. Main function of Golgi apparatus is protein sorting, packaging and secretion.
The finished products may have any one of the following destinations: They may pass through plasma membrane to the surrounding medium. This forms continuous secretion, e. They reach plasma membrane and form an integral part of it, but not secreted. They are formed into a secretory vesicle, where these products are stored for a longer time.
Under appropriate stimuli, the contents are secreted. Release of trypsinogen by pancreatic. Lipid hydrolysing enzymes fatty acyl esterase, phospholipases. Endoplasmic Biosynthesis of proteins, glycoproteins, reticulum lipoproteins, drug metabolism, ethanol oxidation, synthesis of cholesterol partial Golgi body Lysosome Maturation of synthesized protein Degradation of proteins, carbohydrates, lipids and nucleotides.
Mitochondria Electron transport chain, ATP generation, TCA cycle, beta oxidation of fatty acids, ketone body production, urea synthesis part , heme synthesis part , gluconeogenesis part , pyrimidine synthesis part Cytosol Protein synthesis, glycolysis, glycogen metabolism, HMP shunt pathway, transaminations, fatty acid synthesis, cholesterol synthesis, heme synthesis part , urea synthesis part , pyrimidine synthesis part , purine synthesis.
The peroxisomes have a granular matrix. They are of 0. They contain peroxidases and catalase. They are prominent in leukocytes and platelets. The free radicals damage molecules, cell membranes, tissues and genes. Chapter Catalase and peroxidase are the enzymes present in peroxisomes which will destroy the unwanted peroxides and other free radicals. Clinical applications of peroxisomes are shown in Box 2. They are spherical, oval or rod-like bodies, about 0. Clinical Applications of Lysosomes 1.
In gout, urate crystals are deposited around knee joints Chapter These crystals when phagocytosed, cause physical damage to lysosomes and release of enzymes. Inflammation and arthritis result. Following cell death, the lysosomes rupture releasing the hydrolytic enzymes which bring about postmortem autolysis.
Lysosomal proteases, cathepsins are implicated in tumor metastasis. Cathepsins are normally restricted to the interior of lysosomes, but certain cancer cells liberate the cathepsins out of the cells. Then cathepsins degrade the basal lamina by hydrolysing collagen and elastin, so that other tumor cells can travel out to form distant metastasis.
There are a few genetic diseases, where lysosomal enzymes are deficient or absent. This leads to accumulation of lipids or polysaccharides Chapters 10 and Silicosis results from inhalation of silica particles into the lungs which are taken up by phagocytes.
Lysosomal membrane ruptures, releasing the enzymes. This stimulates fibroblast to proliferate and deposit collagen fibers, resulting in fibrosis and decreased lungs elasticity. Inclusion cell I- cell disease is a rare condition in which lysosomes lack in enzymes, but they are seen in blood.
This means that the enzymes are synthesized, but are not able to reach the correct site. It is shown that mannose-6phosphate is the marker to target the nascent enzymes to lysosomes. In these persons, the carbohydrate units are not added to the enzyme. Mannosephosphatedeficient enzymes cannot reach their destination protein targetting defect.
The synthesized materials may be collected into lysosome packets. Discovered in by Rene de Duve Nobel prize , lysosomes are tiny organelles.
Solid wastes of a township are usually decomposed in incinerators. Inside a cell, such a process is taking place within the lysosomes. They are bags of enzymes. Clinical applications of lysosomes are shown in Box 2. Endocytic vesicles and phagosomes are fused with lysosome primary to form the secondary lysosome or digestive vacuole. Foreign particles are progressively digested inside these vacuoles. Completely hydrolysed products are utilized by the cell.
As long as the lysosomal membrane is intact, the encapsulated enzymes can act only locally. But when the membrane is disrupted, the released enzymes can hydrolyse external substrates, leading to tissue damage. The lysosomal enzymes have an optimum pH around 5. These enzymes are a. Polysaccharide hydrolysing enzymes alpha-glucosidase, alpha-fucosidase, beta-galactosidase, alphamannosidase, beta-glucuronidase, hyaluronidase, aryl sulfatase, lysozyme b Protein hydrolysing enzymes cathepsins, collagenase, elastase, peptidases c.
Nucleic acid hydrolysing enzymes ribonuclease, deoxyribonuclease. Mitochondria Fig. Erythrocytes do not contain mitochondria. The tail of spermatozoa is fully packed with mitochondria. Mitochondria are the powerhouse of the cell, where energy released from oxidation of food stuffs is trapped as chemical energy in the form of ATP Chapter Metabolic functions of mitochondria are shown in Table 2. Mitochondria have two membranes.
The inner membrane convolutes into folds or cristae Fig. The inner mitochondrial membrane contains the enzymes of electron transport chain Chapter The fluid matrix contains the enzymes of citric acid cycle, urea cycle and heme synthesis. Cytochrome P system present in mitochondrial inner membrane is involved in steroidogenesis Chapter Superoxide dismutase is present in cytosol and mitochondria Chapter Box 2.
Peroxisomal Deficiency Diseases 1. Deficiency of peroxisomal matrix proteins can lead to adreno leuko dystrophy ALD Brown-Schilders disease characterized by progressive degeneration of liver, kidney and brain. It is a rare autosomal recessive condition. In Zellweger syndrome, proteins are not transported into the peroxisomes.
This leads to formation of empty peroxisomes or peroxisomal ghosts inside the cells. Protein targetting defects are described in Chapter Primary hyperoxaluria is due to the defective peroxisomal metabolism of glyoxalate derived from glycine Chapter Proteins are anchored in the membrane by different mechanisms 5.
Mitochondria also contain specific DNA. The integral inner membrane proteins, are made by mitochondrial protein synthesising machinery. However the majority of proteins, especially of outer membrane are synthesised under the control of cellular DNA.
The division of mitochondria is under the command of mitochondrial DNA. Mitochondrial ribosomes are different from cellular ribosomes.
Antibiotics inhibiting bacterial protein synthesis do not affect cellular processes, but do inhibit mitochondrial protein biosynthesis Chapter Taking into consideration such evidences, it is assumed that mitochondria are parasites which entered into cells at a time when multicellular organisms were being evolved.
These parasites provided energy in large quantities giving an evolutionary advantage to the cell; the cell gave protection to these parasites. This perfect symbiosis, in turn, evolved into a cellular organelle of mitochondria.
A summary of functions of organelles is given in Table 2. Comparison of Cell with a Factory Plasma membrane Nucleus Endoreticulum Golgi apparatus Lysosomes Vacuoles Mitochondria Fence with gates; gates open when message is received Managers office Conveyer belt of production units Packing units Incinerators Lorries carrying finished products. The lipid bilayer shows free lateral movement of its components, hence the membrane is said to be fluid in nature. Fluidity enables the membrane to perform endocytosis and exocytosis.
However, the components do not freely move from inner to outer layer, or outer to inner layer flip-flop movement is restricted. During apoptosis programmed cell death , flip-flop movement occurs.
This Flip-flop movement is catalyzed by enzymes.
Flippases catalyse the transfer of amino phospholipids across the membrane. Floppases catalyse the outward directed movement which is ATP dependent. This is mainly seen in the role of ABC proteins mediating the efflux of cholesterol and the extrusion of drugs from cells. The MDR multi drug resistance associated p-glycoprotein is a floppase. Ernst Ruska designed the first electron microscope in Gerd Binning and Heinrich Rohrer introduced the scanning electron microscopy in by which the outer and inner layers of membranes could be visualized separately.
All the three workers were awarded Nobel prize in The plasma membrane separates the cell from the external environment. It has highly selective permeability properties so that the entry and exit of compounds are regulated. The cellular metabolism is in turn influenced and probably regulated by the membrane. The membrane is metabolically very active.
The enzyme, nucleotide phosphatase 5' nucleotidase and alkaline phosphatase are seen on the outer part of cell membrane; they are therefore called ecto-enzymes. Membranes are mainly made up of lipids, proteins and small amount of carbohydrates. The contents of these compounds vary according to the nature of the membrane. The carbohydrates are present as glycoproteins and glycolipids. Phospholipids are the most common lipids present and they are amphipathic in nature.
Cell membranes also contain cholesterol. Later, the structure of the biomembranes was described as a fluid mosaic model Singer and Nicolson, The phospholipids are arranged in bilayers with the polar head groups oriented towards the extracellular side and the cytoplasmic side with a hydrophobic core Fig. The distribution of the phospholipids is such that choline containing phospholipids are mainly in the external layer and ethanolamine and serine containing phospholipids in the inner layer.
Each leaflet is 25 thick, with the head portion 10 and tail 15 thick. The total thickness is about 50 to The cholesterol content of the membrane alters the fluidity of the membrane. When cholesterol concentration increases, the membrane becomes less fluid on the outer surface, but more fluid in the hydrophobic core. The effect of cholesterol on membrane fluidity is different at different temperatures.
At temperature below the Tm cholesterol increases fluidity and there by permeability of the membrane. At temperatures above the Tm, cholesterol decreases fluidity. In spur cell anemia and alcoholic cirrhosis membrane studies have revealed the role of excess cholesterol. The decrease in membrane fluidity may affect the activities of receptors and ion channels.
Fluidity of cellular membranes responds to variations in diet and physiological states. Increased release of reactive oxygen species ROS , increase in cytosolic calcium and lipid peroxidation have been found to adversely affect membrane fluidity. Anesthetics may act by changing membrane fluidity. The nature of the fatty acids also affects the fluidity of the membrane, the more unsaturated cis fatty acids increase the fluidity.
The fluidity of the membrane is maintained by the length of the hydrocarbon chain, degree of unsaturation and nature of the polar head groups. Trans fatty acids TFA decrease the fluidity of membranes due to close packing of hydrocarbon chains. Cis double bonds create a kink in the hydrocarbon chain and have a marked effect on fluidity. Second OH group of. Chemical Basis of Life glycerol in membrane phospholipids is often esterified to an unsaturated fatty acid, mono unsaturated oleic or polyunsaturated linoleic, linolenic or arachidonic.
The nature of fatty acids and cholesterol content varies depending on diet. A higher proportion of PUFA which increases the fluidity favors the binding of insulin to its receptor, a trans membrane protein.
The endocytosis of cholesterol containing lipoproteins may be caveolae mediated. Similarly the fusion and budding of viral particles are also mediated by caveolae. Membrane Proteins 5-A. The peripheral proteins exist on the surfaces of the bilayer Fig. They are attached by ionic and polar bonds to polar heads of the lipids.
Anchoring of proteins to lipid bilayers: Several peripheral membrane proteins are tethered to the membranes by covalent linkage with the membrane lipids. Since the lipids are inserted into the hydrophobic core, the proteins are firmly anchored.
A typical form of linkage is the one involving phosphatidyl inositol which is attached to a glycan. This glycan unit has ethanolamine, phosphate and several carbohydrate residues. This glycan chain includes a glucose covalently attached to the C terminus of a protein by the ethanolamine and to the phosphatidyl inositol by the glucosamine.
The fatty acyl groups of the phosphatidyl inositol diphosphate PIP2 are firmly inserted into the lipid membrane thus anchoring the protein.
This is referred to as glycosyl phosphatidyl inositol GPI anchor. Microdomains on membranes: GPI anchored proteins are often attached to the external surface of plasma membrane at microdomains called lipid rafts. They are areas on the membrane having predominantly glycosphingolipids and cholesterol.
The localization and activity of the protein can be regulated by anchoring and release. Lipid rafts have a role in endocytosis, G protein signaling and binding of viral pathogens. The GPI anchors that tether proteins to the membrane are also seen at the lipid rafts.
Membrane proteins may be anchored by covalent bonding, palmitoylation and myrystoylation. Caveolae are flask shaped indentations on the areas of lipid rafts that are involved in membrane transport and signal transduction. Caveolae contain the protein caveolin, along with other receptor proteins. Transport of macromolecules IgA from the luminal side occurs. The integral membrane proteins are deeply embedded in the bilayer and are attached by hydrophobic bonds or van der Waals forces.
Some of the integral membrane proteins span the whole bilayer and they are called transmembrane proteins Fig. The hydrophobic side chains of the amino acids are embedded in the hydrophobic central core of the membrane.
The transmembrane proteins can serve as receptors for hormones, growth factors, neurotransmitters , tissue specific antigens, ion channels, membrane-based enzymes, etc. Bacterial Cell Wall Prokaryotic bacterial cells as well as plant cells have a cell wall surrounding the plasma membrane; this cell wall provides mechanical strength to withstand high osmotic pressure.
Animal cells are devoid of the cell wall; they have only plasma membrane. Major constituent of bacterial cell wall is a heteropolysaccharide, consisting of repeating units of N-acetyl muramic acid NAM and N-acetyl glucosamine NAG. This polysaccharide provides mechanical strength to the plasma membrane. Synthesis of this complex polysaccharide is blocked by penicillin. This inhibition is responsible for the bactericidal action of penicillin. This tight junction permits calcium and other small molecules to pass through from one cell to another through narrow hydrophilic pores.
Some sort of communication between cells thus results. Absence of tight junction is implicated in loss of contact inhibition in cancer cells Chapter Tight junctions also seal off subepithelial spaces of organs from the lumen.
They contain specialized proteins such as occludin, claudins and other adhesion molecules. Chapter 2; Subcellular Organelles and Cell Membranes 13 chromosomal movements during cell division. The cytoskeleton is made up of a network of microtubules Fig. Tubules consist of polymers of tubulin. Molecular Motors Proteins that are responsible for co-ordinated movements in tissues and cells are referred to as molecular motors.
These may be ATP driven as in the case of the contractile proteins; actin and myosin in muscle as well as dyenin and tubulin in cilia and flagella. Kinesin which mediates movement of vesicles on microtubules also requires ATP. Water channel or aquaporin Myelin Sheath It is made up of the membrane of Schwann cells Theodor Schwann, condensed and spiralled many times around the central axon.
The cytoplasm of Schwann cells is squeezed to one side of the cell. Myelin is composed of sphingomyelin, cholesterol and cerebroside. Myelin sheaths thin out in certain regions Node of Ranvier Anotoine Ranvier, Due to this arrangement, the propagation of nerve impulse is wavelike; and the speed of propagation is also increased. Upon stimulation, there is rapid influx of sodium and calcium, so that depolarization occurs. Voltage gradient is quickly regained by ion pumps.
The ions flow in and out of membrane only where membrane is free of insulation; hence the wave-like propagation of impulse. In multiple sclerosis, demyelination occurs at discrete areas, velocity of nerve impulse is reduced, leading to motor and sensory deficits.
Microvilli Microvilli of intestinal epithelial cells and pseudopodia of macrophages are produced by membrane evagination. This is due to the fluid nature of membranes. Membranes of Organelle Membranes of endoplasmic reticulum, nucleus, lysosomes and outer layer of mitochondria may be considered as variants of plasma membrane. Cytoskeleton Human body is supported by the skeletal system; similarly the structure of a cell is maintained by the cytoskeleton present underneath the plasma membrane. The cytoskeleton is responsible for the shape of the cell, its motility and.
Water soluble compounds are generally impermeable and require carrier mediated transport. An important function of the membrane is to withhold unwanted molecules, while permitting entry of molecules necessary for cellular metabolism. Transport mechanisms are classified into 1. Passive transport 1-A. Simple diffusion 1-B. Facilitated diffusion. Ion channels are specialized carrier systems. They allow passage of molecules in accordance with the concentration gradient.
Active transport 3. Pumps can drive molecules against the gradient using energy. Simple Diffusion Solutes and gases enter into the cells passively.
They are driven by the concentration gradient. The rate of entry is proportional to the solubility of that. Simple diffusion occurs from higher to lower concentration. This does not require any energy. However, it is a very slow process. Facilitated Diffusion This is a carrier mediated process Fig. Important features of facilitated diffusion are: The carrier mechanism could be saturated which is similar to the Vmax of enzymes.
Structurally similar solutes can competitively inhibit the entry of the solutes. Facilitated diffusion can operate bidirectionally. This mechanism does not require energy but the rate of transport is more rapid than simple diffusion process. The carrier molecules can exist in two conformations, Ping and Pong states. In the pong. Then there is a conformational change.
In the ping state, the active sites are facing the interior of the cell, where the concentration of the solute is minimal. This will cause the release of the solute molecules and the protein molecule reverts to the pong state. By this mechanism the inward flow is facilitated, but the outward flow is inhibited Fig.
Hormones regulate the number of carrier molecules. For example, glucose transport across membrane is by facilitated diffusion involving a family of glucose transporters. Glucose transport is described in detail in Chapter 9. Aquaporins They are water channels Fig. They are a family of membrane channel proteins that serve as selective pores through which water crosses the plasma membranes of cells.
They form tetramers in the cell membrane, and facilitate the transport of water They control the water content of cells. Agre and MacKinnon were awarded Nobel prize for chemistry in for their contributions on aquaporins and water channels. Diseases such as nephrogenic diabetes insipidus is due to impaired function of these channels. Channelopathies are a group of disorders that result from abnormalities in the proteins forming the ion pores or channels.
A few examples are cystic fibrosis chloride channel , Liddle's syndrome sodium channel and periodic paralysis potassium channel. Please create a new list with a new name; move some items to a new or existing list; or delete some items. Textbook of Biochemistry for Medical Students.
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